Flaviviridae are a family of RNA viruses with a single stranded positive sense RNA genome. The RNA viral genome plays important roles during viral replication, including as mRNA for viral protein synthesis, a template for RNA replication, and a nascent RNA genome for a newly formed virus. The family includes the genera Flavivirus, Hepacivirus, Hepatitis G Virus, and Pestivirus.
Major diseases caused by Flaviviridae include hepatitis C, Dengue fever, West Nile encephalitis, Tick-borne encephalitis, and Yellow fever.
Hepatitis C(HCV) is a Hepacivirus. It is estimated that 75% of all cases of liver disease is caused by HCV. HCV infection can lead to cirrhosis and liver cancer and can become so serious that a liver transplant is required. Approximately 170-200 million people worldwide are infected, with 3-5 million in the United States.
The HCV non-structural protein NS5B RNA-dependent RNA polymerase is a key component of the replicative complex and is responsible for initiating and catalyzing viral RNA synthesis. As a result, the HCV NS5B is an attractive target for the current drug discovery and development of anti-HCV agents. There are two major subclasses of NS5B inhibitors: nucleoside analogs, which are anabolized to their active triphosphates, and which act as alternative substrates for the polymerase, and non-nucleoside inhibitors (NNIs), which bind to allosteric regions on the protein. Nucleoside or nucleotide inhibitors mimic natural polymerase substrate and act as chain terminators. They inhibit the initiation of RNA transcription and elongation of a nacent RNA chain.
Other HCV proteins that are targets for therapeutic approaches are NS3/4A (a serine protease) and NS5A (a non-structural protein that is an essential component of HCV replicase and exerts range of effects on cellular pathways).
Current approved therapies for HCV include interferon alpha-2b or pegylated interferon alpha-2b (Pegintron), which is administered with ribavirin (Rebetol), and NS3/4A protease inhibitors telaprevir (Incivek, Vertex and Johnson & Johnson) and boceprevir (Victrelis, Merck).
Several NS5B nucleoside/nucleotide polymerase inhibitors have been in clinical trials (shown in FIG. 1). 2′-C-methylcytidine (NM107), the valine ester of 2′-C-methylcytidine (valocitabine, NM283), was the first polymerase inhibitors in clinical trials and was discontinued due to the GI toxicity. The second nucleoside inhibitor, 4′-C-azido-nucleoside (R1479) as its tri-isobutyl ester prodrug (R1626), has been developed by Roche, however, it was discontinued due to the haematopoetic toxicity. Currently, Roche and Pharmasset are developing R7128 (mericitabine), a prodrug of β-D-2′-deoxy-2′-α-fluoro-2′-C-methylcytidine (PSI6130). Idenix has been developing a purine analogue, 2′-C-methylguanosine monophosphate prodrug (IDX184), however, it is currently under clinical hold due to the potential cardiac toxicity concern by the FDA because of the discontinuation of Inhibitex INX-189 due to cardio-toxicity. A uridine analogue in a prodrug (PSI-7977) form can potently inhibit HCV replication. Recently, a 3′,5′-cyclic phosphate analogue, PSI-938, has also been reported as a potent anti-HCV agent but has been discontinued due to liver toxicity.
Oh et al. published an article on “Design and Synthesis of Novel Carbocyclic Versions of 2′-Spirocyclopropyl ribonucleosides as potent anti-HCV agents.” Oh et al. reported that the synthesized cytosine nucleoside had moderate anti-HCV activity (IC50 of 14.4 in Hu7 cell line).
Gadthula et al. published an article on “Synthesis and antiviral activity of cyclopropy-spirocarbocyclic adenosine (4R,5S,6R,7R)-4-(6-amino-9H-pur-9-yl)-7-(hydroxymethyl)spiro[2.4]heptane-5,6 diol against hepatitis C virus” (Bioorganic & Medicinal Chemistry Letters 21 (2011) 3982-3985). The titled compound exhibited an EC50 of 0.273 and 0.368 μM in genotypes 1A and 1B, respectively in the Hu7 RNA replicon assay.
United States patents which describe nucleoside polymerase inhibitors for the treatment of Flaviviridae, including HCV, include those filed by Idenix Pharmaceuticals (U.S. Pat. Nos. 8,343,937; 8,299,038; 6,914,054; 6,812,219; 7,608,597; 7,902,202; 7,951,789; 7,547,704; 7,456,155; 7,365,057; 7,608,600; 7,635,689; 7,625,875; 7,148,206; 7,163,929; 7,169,766; 7,105,493; and 7,157,441), Merck (U.S. Pat. Nos. 7,125,855; 6,777,395; 7,105,499; and 7,202,224), Gilead Sciences (U.S. Pat. Nos. 7,973,013; 8,324,179; and 8,334,270), Emory University (U.S. Pat. Nos. 6,911,424; 8,168,583; 6,348,587; 7,662,938; and 7,307,065), and Pharmasset Inc. (U.S. Pat. Nos. 7,429,572; 8,093,380; 7,964,580; and 6,949,522).
There remains a strong medical need to develop anti-Flaviviridae, including anti-HCV, therapies that are effective, well-tolerated, and reasonably safe. Given the number of people infected with hepatitis C and the potential severity of the infection, the need is particularly strong. The need is accentuated by the expectation that combination drug therapies may be most efficacious to treat HCV and other Flaviviridae.
It is therefore an object of the present invention to provide compounds, pharmaceutical compositions, and methods and uses to treat and/or prevent infections from Flaviviridae viruses, including Hepatitis C virus, and related conditions and/or disease states as otherwise described herein.